CN108752289B - Synthesis method of 2,2' -hydrazine-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt - Google Patents
Synthesis method of 2,2' -hydrazine-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt Download PDFInfo
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- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
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Abstract
The invention provides a synthesis method of 2,2' -hydrazine-bis (3-ethylbenzothiazoline-6-sulfonic acid) diamine salt (ABTS), belonging to the field of organic synthesis. The 2-hydroxybenzothiazole firstly reacts with 2-bromoethane to generate 3-ethylbenzothiazole-2-ketone, then reacts with hydrazine hydrate to generate 2,2' -azino bis (3-ethylbenzothiazoline), then reacts with concentrated sulfuric acid for sulfonation to generate a compound 2,2' -azino bis (3-ethylbenzothiazoline-6-sulfonic acid), and finally reacts with ammonia gas to generate salt so as to obtain 2,2' -biamino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diamine salt. The method has the advantages of cheap and easily obtained raw materials, simple and convenient operation, mild reaction conditions and high yield.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of 2,2' -hydrazine-bis (3-ethylbenzothiazoline-6-sulfonic acid) diamine salt (ABTS).
Technical Field
The 2,2' -hydrazine-bis (3-ethylbenzothiazoline-6-sulfonic acid) diamine salt (ABTS) can be used for biochemical research, free chlorine spectral reagent, chromogenic substrate of enzyme-linked immunosorbent assay, and substrate of peroxidase for ELISA experiment. An ABTS method, namely Total Antioxidant Capacity Assay Kit with ABTS method, T-AOC Assay Kit for short, is a Kit which adopts ABTS as a color developing agent and can detect the Total Antioxidant Capacity of various body fluids such as blood plasma, blood serum, saliva, urine and the like, lysate such as cells or tissues and the like, plant or Chinese herbal medicine extract or various Antioxidant (Antioxidant) solutions. At present, few reports on the literature about the synthesis of 2,2' -hydrazine-bis (3-ethylbenzothiazoline-6-sulfonic acid) diamine salt (ABTS) are provided, and only the literature showsSynthetic Communications, 2014, vol. 44, # 24, p. 3630–3636In addition to the complete reports, other reports only relate to different synthesis methods of intermediates in the synthesis process of ABTS, and no specific detailed reports of ABTS exist. At present, ABTS is expensive, the synthesis route is limited, and the search for a new optimized synthesis method of ABTS still has great significance, which is also the intention of chemical substance methodology per se.
Disclosure of Invention
The invention aims to provide a method for synthesizing 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS).
The invention provides the following synthesis technical scheme, a synthesis method of 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), and the synthesis route of the invention is as follows:
the method comprises the following steps:
dissolving 2-hydroxybenzothiazole and 2-bromoethane in an organic solvent, and reacting under an alkaline condition to obtain 3-ethylbenzothiazole-2-ketone.
And secondly, dissolving 3-ethylbenzothiazole-2-ketone and hydrazine hydrate in an organic solvent, and heating and refluxing the mixture under the catalysis of hydrochloric acid to react to obtain the 2,2' -dinitrobis (3-ethylbenzothiazoline).
And thirdly, dissolving 2,2 '-dinitrobis (3-ethylbenzothiazoline) in 10% fuming sulfuric acid, and reacting under the ice-water bath condition to obtain 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid).
And fourthly, dissolving the 2,2 '-dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid) in an organic solvent, and reacting with ammonia to obtain 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt.
In the method, the organic solvent in the first step is selected from tetrahydrofuran or acetonitrile; in the second step and in the fourth step, the organic solvent is selected from methanol or ethanol.
In the first step of the method, the molar ratio of 2-hydroxybenzothiazole to 2-bromoethane to alkali is 1: 1.1-1.5: 1-1.5.
In the first step of the method, the used alkali is sodium hydroxide or potassium hydroxide, and the reaction temperature is from room temperature to solvent reflux.
According to the method, after the first-step reaction is finished, hydrazine hydrate can be directly added for the second-step reaction without treatment.
In the second step of the method, the molar ratio of the 3-ethylbenzothiazole-2-ketone, the hydrazine hydrate and the hydrochloric acid is 1: 0.5-0.55: 0.1-0.2.
In the third step of the method, the mass ratio of 2,2' -dinitrobis (3-ethylbenzthiazoline) and 10% fuming sulfuric acid is 1: 5-10.
In the fourth step of the method, ammonia gas can be introduced or ammonia water can be added for reaction.
In the fourth step of the method, the molar ratio of the 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid) to the ammonia is 1: 2-4.
The invention has the beneficial effects that: the novel method for synthesizing the 2,2' -hydrazine-bis (3-ethylbenzothiazoline-6-sulfonic acid) diamine salt (ABTS) has the advantages of low cost, high yield, excellent synthetic route and the like, and the pilot production is already carried out, and a large amount of pilot production is carried out.
Detailed Description
The present invention is described in detail below with reference to specific examples, which are intended to be illustrative of the operation of the present invention and are not intended to be limiting.
Example 1
(1) 2-hydroxybenzothiazole (1mol, 151 g), 2-bromoethane (1.1mol, 120 g) and potassium hydroxide (1mol, 56 g) were dissolved in 2L of tetrahydrofuran, stirred at 0 ℃ for reaction for 1 hour, then reacted at room temperature for 2 hours, after the reaction was completed, the tetrahydrofuran solvent was removed by spinning, 2L of ethyl acetate was added, washed twice with water, dried over anhydrous sodium sulfate, then ethyl acetate was spun off, and crystallized from methyl t-butyl ether to give 150 g of 3-ethylbenzothiazol-2-one in 84% yield. HNMR (DMSO-d 6, 400MHz): 7.67-7.60 (m, 1H), 7.41-7.27 (m, 2H), 7.23-7.14 (m, 1H), 3.97(q, 2 H), 1.19(t,3H).
(2) 3-ethylbenzothiazol-2-one (1mol, 179 g) obtained in step (1) was dissolved in 1000mL of ethanol, followed by addition of 80% hydrazine hydrate (0.625mol, 31 g), heating and refluxing for 4 hours, and TLC detection showed no reaction. Then concentrated hydrochloric acid (0.12mol, 10mL) is added, stirring is continued, precipitation is gradually generated, reaction is continued for 3 hours, cooling, suction filtration and washing with cold ethanol are carried out, so that 153 g of 2,2' -dinitrobis (3-ethylbenzthiazoline) is obtained, and the yield is 86%. H NMR (DMSO-d 6, 400 MHz): 7.53 (d, 1H), 7.26 (t, 1H), 7.18 (d, 1H), 6.99 (t,1H), 4.05 (q, 2H) , 1.27 (t, 3H).
Directly adding hydrazine hydrate without separation after the first-step reaction to carry out a second-step reaction: dissolving 2-hydroxybenzothiazole (1mol, 151 g), 2-bromoethane (1.1mol, 120 g) and potassium hydroxide (1mol, 56 g) in tetrahydrofuran 2L, stirring and reacting at 0 ℃ for 1 hour, then reacting at room temperature for 2 hours, then adding hydrochloric acid to adjust the mixture to be acidic, adding 80% hydrazine hydrate (0.625mol, 31 g), heating and refluxing to generate a solid, cooling after 4 hours, and performing suction filtration to obtain 140 g of 2,2' -biazobis (3-ethylbenzothiazoline) with the yield of 79%.
(3) Slowly adding the 2,2 '-dinitrobis (3-ethylbenzothiazoline) (1mol, 354.5 g) obtained in the step (2) into 1.8L of 10% fuming sulfuric acid in an ice water bath, stirring to room temperature, reacting for 4 hours, slowly pouring the reaction liquid onto crushed ice, continuously stirring, performing suction filtration to obtain a dark blue-green solid, washing the solid twice with a small amount of water, washing off sulfuric acid contained in the solid, and performing suction filtration to dryness to obtain 510 g of a crude product of the 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid), wherein the yield is 99%. H NMR (DMSO-d 6, 400MHz): 7.73 (s, 2H), 7.52-7.50 (m, 2H), 7.12-7.14 (m, 4H), 4.09 (q, 2H), 1.27 (t, 6H).
(4) Dissolving the 2,2 '-diazobis (3-ethylbenzothiazoline-6-sulfonic acid) (1mol, 515 g) obtained in the step (3) in 5L of methanol to obtain a clear dark green solution, introducing ammonia gas under stirring at room temperature to generate solid, after no more solid is generated, after the reaction is finished, performing suction filtration to obtain 450 g of 2,2' -diazobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt ABTS, performing rotary evaporation to remove part of filtrate methanol to obtain 50 g of ABTS, combining the ABTS and the ABTS, and recrystallizing with water to obtain 460 g with the yield of 84%. H NMR (DMSO-d 6, 400MHz): 7.72 (d, 2H), 7.52-7.50 (m, 2H), 7.12 (d, 10H), 4.06 (q, 4H), 1.27 (t, 6H).
Example 2
(1) 2-hydroxybenzothiazole (1mol, 151 g), 2-bromoethane (1.2mol, 131 g) and sodium hydroxide (1.1mol, 44 g) were dissolved in acetonitrile 2L, stirred at 0 ℃ for 1 hour, then reacted at room temperature for 2 hours, after the reaction was completed, the acetonitrile solvent was removed by spinning, 2L of dichloromethane was added, washed twice with water, dried over anhydrous sodium sulfate, then the dichloromethane was spun off, and crystallized from methyl t-butyl ether to give 153 g of 3-ethylbenzothiazol-2-one in 85% yield.
(2) Dissolving the 3-ethylbenzothiazole-2-ketone (1mol, 179 g) obtained in the step (1) in 1000mL of methanol, adding 80% hydrazine hydrate (0.625mol, 31 g), then adding concentrated hydrochloric acid (0.14mol, 12mL), heating and refluxing for 4 hours, after the reaction is finished, cooling, carrying out suction filtration, and washing with cold methanol to obtain 151 g of 2,2' -dinitrobis (3-ethylbenzothiazoline) with the yield of 85%.
(3) Slowly adding the 2,2 '-diazobis (3-ethylbenzothiazoline) (1mol, 354.5 g) obtained in the step (2) into 1.5L of 10% fuming sulfuric acid in ice water bath, stirring to room temperature for reacting for 6 hours, slowly pouring the reaction liquid onto crushed ice, continuously stirring, performing suction filtration to obtain a dark blue-green solid, washing the solid twice with a small amount of water, washing to remove sulfuric acid contained in the solid, and performing suction filtration to dryness to obtain about 511 g of a crude product of the 2,2' -diazobis (3-ethylbenzothiazoline-6-sulfonic acid), wherein the yield is 99%.
(4) Dissolving the 2,2 '-diazobis (3-ethylbenzothiazoline-6-sulfonic acid) (1mol, 515 g) obtained in the step (3) in 5L of methanol to obtain a clear dark green solution, adding 200 g of 25% ammonia water under stirring at room temperature to generate a solid, stirring for 1-2 hours, removing part of methanol after the reaction is finished, performing suction filtration to obtain 490 g of 2,2' -diazobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt ABTS, and recrystallizing with water to obtain 450 g of a pure product with the yield of 82%.
Claims (7)
1. A method for synthesizing 2,2' -hydrazine-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt is characterized in that the reaction equation is as follows:
comprises the following steps:
dissolving 2-hydroxybenzothiazole and 2-bromoethane in an organic solvent, and reacting under an alkaline condition to obtain 3-ethylbenzothiazole-2-ketone; wherein the organic solvent is selected from tetrahydrofuran or acetonitrile; the molar ratio of 2-hydroxybenzothiazole, 2-bromoethane to base is 1: 1.1-1.5: 1-1.5; the alkali is sodium hydroxide or potassium hydroxide, and the reaction temperature is from room temperature to solvent reflux;
secondly, dissolving 3-ethylbenzothiazole-2-ketone and hydrazine hydrate in an organic solvent, and heating and refluxing the mixture under the catalysis of hydrochloric acid to react to obtain 2,2' -dinitro-bis (3-ethylbenzothiazoline);
dissolving 2,2 '-dinitrobis (3-ethylbenzothiazoline) in 10% fuming sulfuric acid, and reacting in an ice-water bath to obtain 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid);
and fourthly, dissolving the 2,2 '-dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid) in an organic solvent, and reacting with ammonia to obtain 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt.
2. The method for synthesizing 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt according to claim 1, wherein the method comprises the following steps: in the second step and in the fourth step, the organic solvent is selected from methanol or ethanol.
3. The method for synthesizing 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt according to claim 1, wherein the method comprises the following steps: in the second step, the mol ratio of the 3-ethylbenzothiazole-2-ketone, the hydrazine hydrate and the hydrochloric acid is 1: 0.5-0.55: 0.1-0.2.
4. The method for synthesizing 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt according to claim 1, wherein the method comprises the following steps: after the first step reaction is finished, hydrazine hydrate is directly added for the second step reaction without separation.
5. The method for synthesizing 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt according to claim 1, wherein the method comprises the following steps: in the third step, the mass ratio of 2,2' -dinitrobis (3-ethylbenzthiazoline) and 10% fuming sulfuric acid is 1: 5-10.
6. The method for synthesizing 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt according to claim 1, wherein the method comprises the following steps: in the fourth step, ammonia gas is introduced or ammonia water is added for reaction with ammonia.
7. The method for synthesizing 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt according to claim 1, wherein the method comprises the following steps: in the fourth step, the molar ratio of 2,2' -dinitrobis (3-ethylbenzothiazoline-6-sulfonic acid) to ammonia is 1: 2-4.
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| CN103073522A (en) * | 2013-01-14 | 2013-05-01 | 江西师范大学 | Synthetic method for 2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt |
| CN103833674A (en) * | 2014-03-13 | 2014-06-04 | 杭州师范大学 | Method for synthesizing 4-methyl-2-diazanyl benzothiazole |
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| EP1731514A1 (en) * | 2005-06-02 | 2006-12-13 | Sandoz AG | Process for the preparation of Pramipexole |
| CN103073522A (en) * | 2013-01-14 | 2013-05-01 | 江西师范大学 | Synthetic method for 2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt |
| CN103833674A (en) * | 2014-03-13 | 2014-06-04 | 杭州师范大学 | Method for synthesizing 4-methyl-2-diazanyl benzothiazole |
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| Two Polymerizable Derivatives of 2,2’-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid);Jiangfeng Fei et al.;《Org. Lett.》;20051207;第8卷(第1期);第3-6页 * |
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